Contributions
Abstract: S245
Type: Oral Presentation
Session title: Stem cell biology and microenvironment
Background
Inflammation is a key component in a complex biological response of the body to harmful stimuli. In the context of the bone marrow (BM), inflammation is an overarching process central to most if not all forms of stress challenges and disease setting. Current research in the field is focused on understanding inflammation in the context of the Hematopoietic Stem Cell (HSC) and its microenvironment response. While such research provides a descriptive understanding of the microenvironment and its interplay, it falls short in translating into functional applications confounded by a single marker approach of classifying the microenvironment cell diversity.
Aims
To utilize the power of single-cell sequencing coupled with functional proliferation readout to investigate inflammation response over time of an unbiased BM microenvironment.
Methods
We studied the murine BM response to IFNα driven inflammatory stress over time (early- 3 hours, mid- 24 hours and late- 72 hours), using single-cell transcriptomics coupled to FACS based proliferation analysis at each time point (n=3/4 for each time point). We utilized the GFP tagged interferon-stimulated gene (ISG) report mouse model to substantiate our findings. Moreover, we validated our findings in multiple BM populations using genetic mouse models lacking crucial IFNα pathway elements (IFNAR-/- and STAT1-/-). Further, to unravel the BM stromal and HSC crosstalk dynamics we performed mouse matched bulk RNA sequencing of the two populations over time (n=3/4 for each time point).
Results
We identify and describe a unique inflammatory-responding Mesenchymal Stromal Cell subset (iMSC) which unlike its BM stromal counterpart responds directly and dynamically to IFNα stimulation. We show that iMSCs specifically produce key inflammation cytokines and secreted factors at the onset of IFNα response (3h). They markedly downregulate Extra Cellular Matrix (ECM) production and thus facilitate microenvironment remodeling at a late time point (24-72h). Using ligand-receptor mapping, we further identified pivotal inflammation-specific interactions between iMSCs and HSCs within the BM.
Conclusion
We propose a distinctive iMSC signature with direct application in unraveling inflammation dynamics of the BM microenvironment. The proposed iMSC signature has the potential to significantly contribute to our understanding of BM microenvironment perturbations in disease settings, like leukemia and immunodeficiencies.
Keyword(s): Bone marrow stroma, Inflammation, Mesenchymal stem cell, Microenvironment
Abstract: S245
Type: Oral Presentation
Session title: Stem cell biology and microenvironment
Background
Inflammation is a key component in a complex biological response of the body to harmful stimuli. In the context of the bone marrow (BM), inflammation is an overarching process central to most if not all forms of stress challenges and disease setting. Current research in the field is focused on understanding inflammation in the context of the Hematopoietic Stem Cell (HSC) and its microenvironment response. While such research provides a descriptive understanding of the microenvironment and its interplay, it falls short in translating into functional applications confounded by a single marker approach of classifying the microenvironment cell diversity.
Aims
To utilize the power of single-cell sequencing coupled with functional proliferation readout to investigate inflammation response over time of an unbiased BM microenvironment.
Methods
We studied the murine BM response to IFNα driven inflammatory stress over time (early- 3 hours, mid- 24 hours and late- 72 hours), using single-cell transcriptomics coupled to FACS based proliferation analysis at each time point (n=3/4 for each time point). We utilized the GFP tagged interferon-stimulated gene (ISG) report mouse model to substantiate our findings. Moreover, we validated our findings in multiple BM populations using genetic mouse models lacking crucial IFNα pathway elements (IFNAR-/- and STAT1-/-). Further, to unravel the BM stromal and HSC crosstalk dynamics we performed mouse matched bulk RNA sequencing of the two populations over time (n=3/4 for each time point).
Results
We identify and describe a unique inflammatory-responding Mesenchymal Stromal Cell subset (iMSC) which unlike its BM stromal counterpart responds directly and dynamically to IFNα stimulation. We show that iMSCs specifically produce key inflammation cytokines and secreted factors at the onset of IFNα response (3h). They markedly downregulate Extra Cellular Matrix (ECM) production and thus facilitate microenvironment remodeling at a late time point (24-72h). Using ligand-receptor mapping, we further identified pivotal inflammation-specific interactions between iMSCs and HSCs within the BM.
Conclusion
We propose a distinctive iMSC signature with direct application in unraveling inflammation dynamics of the BM microenvironment. The proposed iMSC signature has the potential to significantly contribute to our understanding of BM microenvironment perturbations in disease settings, like leukemia and immunodeficiencies.
Keyword(s): Bone marrow stroma, Inflammation, Mesenchymal stem cell, Microenvironment